The working hypothesis to be tested is that phospholipases C and A2 have a major role in initiating and regulating insulin secretion. According to the hypothesis, glucose is recognized at the plasma membrane by a protein that would then be coupled to phospholipase C. The identity of this protein is unknown but possible candidates include the glucose transporter, a putative glucose receptor, or an enzyme of glycolysis. Aim #1 is to define the molecular mechanism whereby glucose and other secretagogues activate phospholipase C in insulin secretion. Aim#2 is to determine whether novel inositol phospholipids (PIP3) are present in islets and insulin-secreting cells, and whether they have a role in insulin secretion. Aim #3 will define and characterize the role of phospholipase A2 and arachidonic acid accumulation in insulin secretion. Preliminary data show that the muscarinic agonist carbachol stimulates phospholipase A2 and glucose may activate diacylglycerol (DAG) lipase and arachidonate may affect voltage- dependent Ca++ influx.